Herpesviridae - 1
T. Mazzulli, MD, FRCPC
Department of Microbiology
Mount Sinai Hospital
Herpesviridae - Objectives
1. To review the members of the Herpesviridae
family
2. To understand the concepts of primary
infection, latent infection and reactivation
disease
3. To recognize the common clinical
syndromes associated with each virus and
the principles of management
Herpesviridae Family
double stranded DNA viruses with envelope
ubiquitous, world-wide distribution
8 human herpesviruses recognized; species specific
Latency - “once infected, always infected”
- site varies with virus type:
- HSV 1 & 2, VZV - sensory nerve ganglia
- CMV, EBV, HHV6, HHV7 – lymphocytes
Replication occurs in the nucleus of infected cell
Viral DNA remains episomal (i.e. not integrated into
host cell DNA)
Transmission & Seroepidemiology of
Herpesviridae
Mode of Transmission
Virus
HSV 1
HSV 2
VZV
CMV
EBV
HHV6
HHV7
HHV8
Seroprevalence
(%)
Perinatal Transfusion Direct Aerosol Healthy Healthy
Transplant Contact
Children Adults
+
+
20 - 40
50 - 70
+
+
0-5
20 - 50
+
+
+
50 - 75
85 - 95
+
+
+
10 - 30
40 - 70
+
+
+
10 - 30
60 - 90
?
?
+
?
80 - 100 60 - 100
?
?
+
?
40 - 80 60 - 100
?
+
+
?
<3
<3
Straus SE. In: Mandell, Douglas, & Bennett (eds). Principles and Practice of
Infectious Diseases, 6th Ed. 2005;1756-1762
Herpesviridae
Transmission:
do not survive for prolonged periods in the
environment
requires inoculation of fresh virus-containing
body fluid of infected person into susceptible
tissue of uninfected person
may be transmitted during primary or
reactivation infections; often the person
shedding virus is asymptomatic
Herpes Simplex Viruses (HSV)
Characteristic
Urogenital infections
Nongenital infections:
Labialis
Keratitis
Whitlow (hand)
Encephalitis (adult)
Neonatal infection
Transmission
HSV-1
10 - 30%
HSV-2
70 - 80%
80 - 90 %
+
+
+
30 %
primarily
non-genital
10 - 20 %
+
70 %
primarily
genital
Herpes Simplex Virus
• Spread via contact with infected secretions:
• transmission both during lesions or from
asymptomatic excretor
• 1-15% of adults excrete HSV-1 or HSV-2 at
any given time
• efficiency of transmission of HSV-2 is
lower than HSV-1
• Clinical Disease: Primary vs Recurrent
Herpes Simplex Virus - Clinical Manifestations
HSV-1 Primary Infection:
•
•
•
•
incubation period 2 to 12 days
usually asymptomatic
gingivostomatitis, pharyngitis
multiple small vesicles in clusters or
singly
• resolves in 10-14 days
Herpes Simplex Virus - Clinical
Manifestations
HSV-2 Primary Infection:
• incubation period 2 - 7 days
• vesicular lesions anywhere in genital tract
• may be associated with fever, malaise, anorexia,
tender bilateral inguinal adenopathy
• lesions may ulcerate; very painful; if involves
urethra may lead to urinary retention
• lesions may persist for weeks
Epidemiology of HSV Infections
Only 10-15% of HSV-2 primary infections are
symptomatic
4 out of every 5 people with genital herpes have not
been diagnosed; three out of five people have
symptoms that are unrecognized as genital herpes
Recurrent disease can be either symptomatic or
asymptomatic
Primary herpes, male
Herpes, female
Herpes cervicitis
Herpes Simplex Virus - Clinical Manifestations
Recurrent Infection:
• common with both HSV-1 and HSV-2: due to
reactivation of endogenous virus despite
antibodies
• recurrent lip or perioral lesions in 20 - 40 %
• recurrent genital lesions in 60 - 90%
• frequency depends on sex, HSV type, titre of
neutralizing antibody
• precipitating factors include: sunlight, fever,
local trauma, menstruation, emotional stress
Herpes Simplex Virus - Clinical Manifestations
Recurrent Infections:
i) Herpes labialis (“cold sore”) - pain, burning, itching
6 hrs (24 - 48 hrs) before lip lesion
• vesicles to ulcer/crust in 48 hrs; healing within 8 10 days
ii) Genital lesions • pain, itching, burning for several hours before
vesicles appear; healing within 6 - 10 days
HSV – Cold Sore
HSV – Cold Sore
Recurrences of Genital HSV
HSV-2 versus HSV-1 genital herpes rates
– Reactivates 49 days versus 310 days after primary
– 4.5 recurrences per year versus <1
HSV-2 recurrence rates vary widely across people:
– 26% women and 8% of men have none in first year
– 14% women and 26% men: >10 recurrences
Recurrence rates trend down (frequency and severity)
over the long term
HSV-2 shedding: 5-32% of days (40% subclinical)
HSV Complications
CNS infections
Perinatal/Congenital
Herpes Simplex Virus: CNS Infections
Encephalitis:
temporal lobes are the principle target;
hemorrhagic necrosis
all ages, all seasons, both sexes
sudden onset or after flu-like prodrome
may be no signs of HSV elsewhere
Herpes Simplex Encephalitis
CT Scan
Autopsy
Herpes Simplex Virus: CNS Infections
Encephalitis:
MRI may detect earlier changes than CT
untreated, rapid deterioration over few days
with 60-80% mortality; 90% of survivors have
significant neurological sequelae
acyclovir treatment reduces mortality by 50%
Herpes Simplex Virus: CNS Infections
Meningitis:
• most commonly associated with primary HSV-2
infection; less likely with recurrences of genital
herpes
• benign, self-limited (contrast with encephalitis)
• usually affects sexually active young adults
• no neurologic sequelae; not clear if acyclovir
treatment alters course of mild meningitis
HSV – Congenital/Perinatal
Intrauterine infection: rare; follows 10 infection
Perinatal infection:
• 75% are due to HSV 2; acquired during delivery
• many women unaware they are infected; 60 - 80%
have no signs or symptoms of genital herpes at
time of labour (asymptomatic shedders)
• HSV-1 acquired from maternal genital, oral or
breast lesions, paternal or other family member, or
nosocomial infection from other infected babies
HSV – Congenital/Perinatal
Perinatal Infections:
pregnancy is associated with state of immunosuppression: shedding, reactivation,
recurrences
subclinical infection in neonates is uncommon
not all infants of infected mothers will become
infected; depends on 10 (30 – 50% risk) vs
recurrent disease (1 – 3% risk)
HSV – Congenital/Perinatal
Clinical manifestations of perinatal infection:
1. disseminated ± CNS disease (49%)
liver, lungs, eyes, CNS
80 - 85% mortality
2. localized to CNS, skin, eyes, oral cavity (50%)
10 - 40% mortality
3. asymptomatic infection (1%)
HSV – Congenital/Perinatal
Treatment:
Mother - acyclovir relatively contraindicated
during pregnancy
Neonate - acyclovir if mother has active
lesions or prolonged membrane rupture
Prevention:
maternal history, surveillance
if active lesions at time of delivery then Csection indicated
Herpes Simplex Virus - Diagnosis
History and physical examination
Vesicle fluid: culture, EM, immunofluorescence,
molecular (e.g. PCR)
Serology
–
–
–
–
difficult to distinguish HSV-1 and HSV-2; no reliable IgM test
seroprevalence
cannot distinguish 1° infection from recurrent disease
? Value of type-specific serology
Immunoglobulin Response in HSV Infection
• IgM Arrives approximately 7 days before IgG
•IgM can reappear during recurrences
Recurrences
Antibody
IgM
IgG
Detectable Level
0
7d
14d
21d
28d
2m
Time
3m
6m
12m
2yr
3yr
HSV Serology
Patients with Primary
Infection
18% -30% with both
IgG and IgM antibodies
Patients with Recurrent
HSV Infection
65% only IgG
35% both IgG and IgM
Type Specific Antibodies to HSV 1 and 2: Review of Methodology.
Herpes 1998:5 33-38 Ashley R.L.
HSV Type-specific Serology:
Clinical Role?
Why do we need to know who has HSV 2?
A)To stop the epidemic spread of genital herpes. HSV is quickly
and silently spreading at varying rates across Canada and not
just in the high risk populations
B)To permit high risk groups to be able to protect themselves
better. HSV has been shown to increase the chance of acquiring
HIV by two to three fold and accelerate the rate of HIV disease
progression
C)To identify women at risk of acquiring HSV in pregnancy
endangering the baby. HSV is potentially fatal in infants if the
mother is shedding virus at the time of delivery.
D)To provide counseling HSV-2 infected patients can expect
several outbreaks per year and are more likely to benefit from
suppression therapy than HSV-1 patients
E)To determine partner sero-status- 75% of source partners find
out about their own infection only when their newly-infected
partner is diagnosed
When should we test for HSV 2?
Symptomatic patients: Use to supplement virus detection tests when:
– Lesions are negative or not sampled for virus
– Recurring symptoms suggest atypical or undiagnosed herpes
– Lesions appear herpetic but may have other etiology
High risk patients but not symptomatic:
– Patient has history of symptoms
– Patient’s partner has genital herpes
– Patient has a history of other STDs
– Patient is at risk of HIV infection
Pregnancy:
– To screen for HSV-2 unrecognized infection
– To determine risk of acquiring infection
– To determine partner’s status for treatment and counseling
Herpes Simplex Virus - Prevention and
Treatment
i) Supportive
– education, psychological support, analgesics, keep
area clean and dry
ii) Antiviral (Acyclovir / Famciclovir / Valacyclovir)
– topical, oral, intravenous
– all effective in 1° genital herpes shedding /
duration
– minimal effect on recurrent attacks
– pattern and natural history not affected
– suppressive (oral) therapy for severe and/or frequent
attacks; once stopped, episodes may recur
iii) No vaccine
Human herpes virus type 6 (HHV - 6)
• isolated in 1988
• roseola infantum - fever x 3 - 4 days: resolves
•
•
•
•
followed by rash
many infections are asymptomatic
diagnosis - clinical; serology
treatment is symptomatic
latent within lymphoid tissue; ? reactivation disease
HHV-6: Roseola Infantum
Common Childhood Infections
Epstein Barr Virus (EBV)
• most childhood infections are asymptomatic
• teens, adults - infectious mono (“kissing disease”)
• incubation period 4 - 7 weeks
• spread by intimate contact with saliva
• fever, lymphadenopathy, fatigue, sore throat,
hepatosplenomegaly, atypical lymphocytes
• resolves 2 - 3 wks but may take months
• latent in lymphoid tissue; ? Reactivation disease
• associated with Burkitt’s lymphoma and nasopharyngeal carcinoma
Epstein Barr Virus (EBV)
Diagnosis:
•
monospot (heterophile antibodies)
•
serology IgM, IgG
•
isolation - not done
Treatment:
•
treatment is supportive; protect spleen
from trauma
•
no vaccine
Cytomegalovirus (CMV)
Transmission:
1) Sexual
2) Perinatal / Intrauterine
3) Blood / Blood product transfusion
4) Organ / tissue transplantation
5) Close contact
• most infections transmitted asymptomatically
Cytomegalovirus (CMV) - Clinical Manifestations
acute infection is usually asymptomatic or mild;
may present as “mono-like” illness and / or
hepatitis
severe disease in:
AIDS
- 25% develop site or life threatening
disease
- >90% infected at autopsy
Transplants - 20 - 60% develop infection
Neonates
- CMV isolated in urine of 1:100
infants
Cytomegalovirus (CMV)
Intrauterine (Congenital) Infections:
symptoms present in <25% of infected infants
cytomegalic inclusion disease (CID) - jaundiced,
hepatosplenomegaly, petechial rash,
microcephaly, cerebral calcifications,
chorioretinitis
may develop symptoms (hearing loss,
behavioral changes, mental retardation) years
later
Cytomegalovirus (CMV)
Diagnosis:
Culture - slow growing, may take weeks for
virus to grow
Electron microscopy - morphology of herpes
viruses
Immunofluoresence techniques
Serology - IgM for acute infection
- IgG for past infection
PCR, DNA hybridization
Cytomegalovirus (CMV)
Treatment:
Immunocompetent patients:
None
Immunocompromised patients:
Ganciclovir
Foscarnet
Prevention:
No vaccine